Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Rα-/- mice

Abstract

Interleukin-2 (IL-2) receptor α knockout (IL-2Rα -/-) mice have a deficiency of CD25 and a corresponding functional defect in T regulatory cells (Tregs). These mice spontaneously develop portal inflammation with biliary ductular damage and colitis with features similar to human inflammatory bowel disease with T cell infiltrates in both the liver and colon. In humans, inflammatory bowel disease may be accompanied by primary sclerosing cholangitis (PSC), but seldom primary biliary cirrhosis (PBC). We hypothesized that the effector mechanism responsible for T cell infiltrates would differ for colon versus liver. To address this thesis, we developed three colonies of double-knockout mice including IL-2Rα-/- CD4-/-, IL-2Rα-/- CD8-/-, and IL-2Rα-/- T cell receptor (TCR)-β-/-. Tissue immunopathology, body weight, and serum levels of cytokines, immunoglobulins, and anti-mitochondrial antibodies (AMA) were assayed at 3 months of age. Relative to IL-2Rα-/- mice, IL-2Rα-/- CD4-/- mice had increased biliary ductular damage but reduced inflammation in the colon. In contrast, IL-2Rα-/- CD8-/- mice had increased colon in.ammation but markedly attenuated biliary ductular damage. Both IL-2Rα-/- CD4-/- and IL-2Rα-/- CD8-/- mice demonstrated elevated serum levels of tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-12p40 (IL-12p40), and interleukin-2 (IL-2) compared with C57BL/6J controls, but only IL-2Rα-/- CD8-/- mice had increased serum levels of immunoglobulin A (IgA), AMA and interleukin-17 (IL-17). Finally, and of importance, IL-2Rα-/- TCR-β -/- mice had abrogation of liver and colon pathological conditions and lacked AMA. In conclusion, on loss of Treg function in mice, CD8T cells mediate biliary ductular damage whereas CD4 T cells mediate induction of colon-specific autoimmunity. Copyright © 2008 by the American Association for the Study of Liver Diseases.